Crisis In Sickle Cell Disease Research Articles

Validation of Patient-Reported Vaso-Occlusive Crisis Day As a Potential Endpoint in Studies of Sickle Cell Disease

Validation of Patient-Reported Vaso-Occlusive Crisis Day As a Potential Endpoint in Studies of Sickle Cell Disease

Phytomedicines (medicines derived from plants) for sickle cell disease.

Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an updated version of a previously published Cochrane Review. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International StandardRandomised Controlled Trial NumberRegister (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 17 March 2020; ISRCTN: 19 April 2020; AMED: 18 May 2020; ClinicalTrials.gov: 24 April 2020; and the WHO ICTRP: 27 July 2017. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Three trials (212 participants) of three phytomedicines: Niprisan® (also known as Nicosan®), Ciklavit® and a powdered extract of Pfaffia paniculata were included. The Phase IIB (pivotal) trial suggests that Niprisan® may be effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not appear to affect the risk of severe complications or the level of anaemia (low-quality evidence). The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). We are uncertain of the effect of Pfaffia paniculata on the laboratory parameters and symptoms of SCD (very low-quality of evidence). No adverse effects were reported with Niprisan® and Pfaffia paniculata (low- to very low-quality evidence). While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in managing people with SCD and the results of its multicentre trials are awaited. Currently, no conclusions can be made regarding the efficacy of Ciklavit® and the powdered root extract of Pfaffia paniculata in managing SCD. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of the three trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials with improved study design and data collection are required on the safety and efficacy of phytomedicines used in managing SCD.

Influence of rs1042713 and rs1042714 polymorphisms of β2-adrenergic receptor gene with erythrocyte cAMP in sickle cell disease patients from Odisha State, India.

The vaso-occlusive crisis (VOCs) in sickle cell disease (SCD) is often associated with stress. Epinephrine released during stress acts via beta 2-adrenergic receptors (β2-AR or ADRB2) to stimulate the synthesis of cyclic adenosine monophosphate (cAMP) in the red blood cells (RBCs). Higher cAMP levels promote adhesion of sickled RBCs to vascular endothelium, a major contributor for VOCs. Several single-nucleotide polymorphisms (SNPs) of the β2-AR gene have been reported; two of them at codon 16 (rs1042713) and codon 27 (rs1042714) have been extensively studied for their clinical relevance. Therefore, we assessed the influence of polymorphism at these two sites of the β2-AR gene on the RBC cAMP concentrations with and without epinephrine stimulation in SCD subjects. We determined the frequency distribution of different genotypes of codon 16 and codon 27 of the β2-AR gene using the Sanger sequencing method in the SCD subjects. We measured the RBC-cAMP levels at baseline and after stimulation with epinephrine, to ascertain the influence of different genotypes in determining cAMP levels. There was no difference in the socio-demographic and hematological indicators in different genotypes of both codon 16 and 27. In the sham-treated erythrocytes, the cAMP levels were significantly different with three genotypes of codon 16 (F = 3.39, P = 0.036; one way ANOVA) but not with different genotypes of codon 27. A significant increase in cAMP levels was noticed with epinephrine treatment in all genotypes of codons 16 and 27 (P = 0.001; Wilcoxon signed-rank test). However, the extent of increase in the epinephrine-treated cAMP values from the sham-treated (baseline) cAMP values was significantly different between the three genotypes of codon 16 (H = 8.74; P = 0.012; Kruskal-Wallis test) but not in codon 27 genotypes. Polymorphism in codon 16 (rs1042713) of the β2-AR gene influences cAMP concentrations in the RBC both before and after epinephrine treatment. Higher cAMP levels may lead to increased adhesion of sickle cell RBCs to vascular endothelium and may increase the frequency of VOCs.

Potential causal role of l-glutamine in sickle cell disease painful crises: A Mendelian randomization analysis

In a recent clinical trial, the metabolite l-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To support this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a potential causal relationship between l-glutamine levels and painful crises (N = 1278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52–0.89], P = 0.0048). In two smaller SCD cohorts (N = 299 and 406), the protective effect of l-glutamine was observed (OR = 0.82 [0.50–1.34]), although the MR result was not significant (P = 0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid were associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

Risk factors for complications after abdominal surgery in children with sickle cell disease

BackgroundAbdominal surgery in children with sickle cell disease (SCD) carries an increased risk of postoperative complications. Preoperative transfusions are frequently given to decrease the risk of vasoocclusive events. However, risk factors for postoperative complications are not well-defined in the pediatric population. MethodsPediatric patients with SCD undergoing common abdominal operations were identified from the National Surgical Quality Improvement Program–Pediatric (NSQIP-P) database from 2012 to 2018. Outcomes of interest were the incidence rates of 1) any complication or readmission, and 2) serious SCD-related complications (stroke, new onset seizure, ventilator support >24 h postoperatively, or readmission with SCD crisis within 30 days of surgery).Patients were categorized by transfusion approach (transfusion within 48 h before surgery vs. no transfusion) and preoperative hematocrit (<21.0, 21.0–23.9, 24.0–26.9, 27.0–29.9, ≥30.0).Stratified bivariate analyses and multivariable logistic regression were used to identify independent risk factors for complications. ResultsA total of 813 patients met inclusion criteria. There were 470 cholecystectomy, 251 splenectomy, 39 appendectomy, and 53 combination procedures; 13% of cases were urgent or emergent. Preoperative hematocrit levels were <21.0 in 3%, 21.0–23.9 in 10%, 24.0–26.9 in 17%, 27.0–29.9in 30%, and ≥30.0 in 41% of patients; 52% received perioperative transfusion. The 30-day incidences of any complication/readmission and SCD-related complications were 12% and 4%, respectively. On bivariate analyses, urgent/emergent case status was the only significant predictor of complications, carrying risk of 20% and 8% for overall and SCD-related complications, respectively; this finding persisted on multivariable logistic regression (OR 1.83, 95% CI 1.0.2–3.29, p = 0.04). Neither preoperative transfusion nor preoperative hematocrit level was associated with complication risk, although there was a trend toward higher SCD-related complications in patients with preoperative hematocrit <21.0 (p = 0.07). ConclusionIn this large cohort of pediatric SCD patients undergoing abdominal surgery, there was no clear association between postoperative complications and the transfusion approach or the preoperative hematocrit level within the range above 21.0. Urgent/emergent surgical procedures carried a nearly two-fold higher complication risk compared to elective procedures.Future studies should prospectively evaluate preoperative transfusion approaches and compare immediate and delayed operative management to nonoperative management in this population. Level of evidenceIII Retrospective review.

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease

AbstractPersons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.

Severe COVID-19 Is a Microvascular Disease.

Severe COVID-19 Is a Microvascular Disease.

A Multiyear Cross-sectional Study of Guideline Adherence for the Timeliness of Opioid Administration in Children With Sickle Cell Pain Crisis

The National Heart, Lung, and Blood Institute evidence-based guidelines for timeliness of opioid administration for sickle cell disease (SCD) pain crises recommend an initial opioid within 1 hour of arrival, with subsequent dosing every 30 minutes until pain is controlled. No multisite studies have evaluated guideline adherence, to our knowledge. Our objective was to determine guideline adherence across a multicenter network. We conducted a multiyear cross-sectional analysis of children with SCD who presented between January 1, 2016, and December 31, 2018, to 7 emergency departments (EDs) within the Pediatric Emergency Care Applied Research Network. Visits for uncomplicated pain crisis were included, defined with an International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 code for SCD crisis and receipt of an opioid, excluding visits with other SCD complications or temperature exceeding 38.5°C (101.3°F). Times were extracted from the electronic record. Guideline adherence was assessed across sites and calendar years. A total of 4,578 visits were included. The median time to first opioid receipt was 62 minutes (interquartile range 42 to 93 minutes); between the first and second opioid receipt, 60 minutes (interquartile range 39 to 93 minutes). Overall, 48% of visits (95% confidence interval 47% to 50%) were guideline adherent for first opioid. Of 3,538 visits with a second opioid, 15% (95% confidence interval 14% to 16%) were guideline adherent. Site variation in adherence existed for time to first opioid (range 22% to 70%) and time between first and second opioid (range 2% to 36%; both P<.001). There was no change in timeliness to first dose or time between doses across years (P>.05 for both). Guideline adherence for timeliness of SCD treatment is poor, with half of visits adherent for time to first opioid and one seventh adherent for second dose. Dissemination and implementation research/quality improvement efforts are critical to improve care across EDs.

P10 An audit to assess the prescribing of analgesia in children who present with pain crisis due to Sickle Cell Disease (SCD)

AimTo assess the prescribing of analgesia to manage pain crises in children with SCD. This was to establish whether the Trust was meeting national and local standards. Prompt pain control is essential to reduce length of stay and further complications.1Standards100% of admissions will be prescribed regular paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) at the recommended frequency unless contraindicated in accordance with national guidance.2 3100% of admissions will be prescribed appropriate doses of analgesia with consideration to weight and age in accordance with local policy.4MethodThe audit was registered with the Trust’s audit committee. A list of paediatric patients with the diagnosis of SCD was sought from paediatricians with an interest in haematology. A data collection form was created. Data was collected retrospectively over a one-year period. A total of 60 admissions were reviewed to check whether analgesia was prescribed regularly at the recommended frequency, and at the correct dose. Results were analysed using descriptive statistical analysis. Exclusion criteria included patients with hospital admissions under 24 hours.ResultsA total of 55 admissions were included in the final sample. The audit showed the Trust was non-adherent to both standards assessed. A total of 45% (95% CI [31.9%, 58.1%]) of admissions were prescribed regular analgesia. A total of 78% (95% CI [67.9%, 88.9%] of admissions were prescribed appropriate doses of analgesia. Two main reasons were found as to why analgesia was prescribed at the incorrect dose. This was due to incorrect weights recorded on the electronic system (n=4) and doses based on age only (n=8).ConclusionThe results show prescribers are familiar with the correct doses of analgesia but fail to prescribe analgesia regularly. This highlights an opportunity for education and training in the management of pain crisis in SCD. One recommendation includes development of an integrated care pathway booklet for paediatric patients presenting with pain crisis due to SCD. Integrated care pathway booklets have been implemented for other conditions such as cystic fibrosis yielding positive outcomes. The results have highlighted key issues surrounding the electronic prescribing system such as out-of-date weights remaining on the system unless updated, and default treatment protocols. The electronic prescribing system requires refinement for use within paediatrics. One suggestion includes compulsory weight field on admission. Limitations of this audit included small sample size. There was a lack of data to make suggestions based on different ages.ReferencesRees D, Olujohungbe A, Parker N, et al. Guidelines for the management of the acute painful crises in sickle cell disease. Br J Haemato 2003;120:744–752.National Institute for Health and Care Excellence (2012) Sickle cell disease: managing acute painful episodes in hospital. NICE Guideline (CG143).Paediatric Formulary Committee. BNF for Children (2018–2019). London: BMJ Group, Pharmaceutical Press, and RCPCH Publications; (2018).General Hospital (2015) Management of sickle cell disease in paediatric patients (CG377).

Adjuvant interventions with opioids for vaso-occlusive crisis in sickle cell disease: A mixed treatment network meta-analysis of randomized controlled clinical trials.

Vaso-occlusive crisis is the most common clinical feature requiring opioid analgesics in patients with sickle cell disease. We conducted a network meta-analysis to compare the drugs that can be used as add-on with opioids for vaso-occlusive crisis. Network meta-analysis of randomized clinical trials. Sickle cell disease patients with vaso-occlusive crisis receiving adjuvants to opioids for pain management. A number of patients with complete pain relief and pain scores assessed either by visual ana-log or by a numerical rating scale were the primary outcomes. Adverse events and dose of opioids (in morphine equiva-lents) for pain alleviation between the treatment arms were the secondary outcome measures. Eleven studies evaluating the addition of ketorolac, magnesium sulfate, ketoprofen, ibuprofen, methadone, inhalational nitric oxide, methylprednisolone, and arginine with morphine were obtained. The pooled analysis showed a favorable effect in the pain reduction for the additions of arginine {-2 [-3.39, -0.61]} and ibuprofen {-1.7 [-3.26, -0.14]} with morphine. Arginine has high probability of being the "best" in the pool followed by ibuprofen. No significant differ-ences were observed in the risk of adverse events {ketoprofen-0.84 [0.42, 1.65]; magnesium sulfate-1.81 [0.64, 5.81]; and arginine-2.08 [0.18, 24.31]}. A significant lower dose of opioid was required when given adjunctive to argin-ine, inhalational nitric oxide, and methylprednisolone. We observed that arginine and ibuprofen could produce additional analgesic effects when combined with morphine in vaso-occlusive crisis.

P-selectin blockade in COVID-19-related ARDS

P-selectin blockade in COVID-19-related ARDS

The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management.

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.

PSY8 HYDROXYUREA (SIKLOS) VERSUS OFF-LABEL GENERIC HYDROXYUREA FOR AVERTING SICKLE CELL-RELATED HOSPITALIZATIONS: A COST-EFFECTIVENESS ANALYSIS

Novel therapeutic options for managing vaso-occlusive crises in pediatric sickle cell disease (SCD) have entered the market recently. However, evidence of their cost-effectiveness is lacking. This study presents a cost-effectiveness analysis of L-glutamine oral powder, hydroxyurea (Siklos) and off-label, generic hydroxyurea; compared to standard of care with chronic blood transfusions. Using a decision-tree model, we compared economic and clinical outcomes of novel SCD drugs and generic hydroxyurea over one-year time horizon in a hypothetical cohort of pediatric (≥ 2 years) SCD patients from a US payer perspective. The main outcome is incremental cost per number of SCD-related hospitalizations averted (ICER). Model inputs were derived from published literature and clinical trials. Drug average wholesale price (AWP) was obtained from Wolters Kluwer Medi-Span®. All costs were converted to 2019 US dollars using the consumer price index (CPI) health care cost component. Off-label, generic hydroxyurea was associated with both reduced costs and higher SCD-related hospitalizations averted, and dominated the novel drugs. L-glutamine oral powder and Siklos had incremental costs of $23,793 and $35,986; and averted 0.4 versus 0.2 SCD-related hospitalizations/year, respectively when compared to standard care. L-glutamine oral powder dominated Siklos. The ICER for L-glutamine oral powder compared to standard care was $55,816 while Siklos cost $153,634/averted SCD-related hospitalization. Generic hydroxyurea and L-glutamine powder, but not Siklos were cost-effective at a willingness-to-pay threshold of $100,000 per SCD-related hospitalization averted. This model was robust to a deterministic one-way sensitivity analysis wherein the hospitalizations prevented in Siklos users was increased by 50%. Generic hydroxyurea remained dominant and the resultant ICER for Siklos was $137,068/SCD-hospitalization averted. The cost-effectiveness of hydroxyurea (SIKLOS) for SCD is dependent on drug cost, budget and willingness-to-pay per sickle cell hospitalization averted. L-glutamine oral powder may represent a cost-effective option for children who fail to respond to generic hydroxyurea.

Quality of life of adolescents living with sickle cell anaemia in Ondo State, Nigeria.

IntroductionThis study assessed the level of knowledge and quality of life of adolescents living with sickle cell disease (SCD) and their quality of life.MethodsThis study utilized descriptive research design. The study was conducted in two secondary level hospitals with functional SCD clinic in Ondo State. One hundred and four (104) adolescents participated in the study. Their consents were sought and gained.ResultsResults showed that more males (63.5%) participated in the study. The mean age of the participants was 15.26±3.09 years. More than half (62.5%) of the participants that participated in the study had SCD crisis within six months. The mean SCD knowledge of participants in the study was 22.12±2.76, while 15.4% of the participants had good knowledge of SCD and Only 13(12.5%) have high quality of life. Also, the mean score of the participants on the quality of life scale was 39.50±6.47.ConclusionKnowledge of adolescents with SCD that participated in the study was relatively low and their quality of life moderate. Effort should therefore, geared towards improving their knowledge about SCD and providing supportive care that will improve their quality of life.

Outcome of short-term emergency department observation care of children with sickle cell disease and vaso-occlusive crises: initial experience from south-western Nigeria.

Short-term emergency department (ED) observation care may prevent prolonged and unnecessary hospital admission in patients with sickle pain. This study highlights the outcomes of short-term ED care of acute pain in children with sickle cell disease (SCD). Children aged 6mo to 19y with SCD and painful crises who were managed by short-term ED care from July 2017 to June 2019 were studied retrospectively. Biodata, pain score, type of care, length of hospital stay, inpatient transfer rate (the proportion that required transfer for full admission) and return rate (the proportion that returned to the hospital for retreatment of unresolved pain) were documented. From July 2017 to June 2019, 122 children with SCD were admitted to the ED for painful crises, of whom 118 (96.7%) with 167 hospital visits were managed by short-term ED observation care. The median length of stay was 10.5h. In 50.3% of encounters, patients were successfully managed without requiring further care. However, in 17.4% of encounters, they had their ED observation care terminated and converted to full admission. The overall return rate for acute care within 1 wk for either persistence of symptoms or any other complaint was 31.7%. Dedicated short-term ED observation care has the potential to provide effective and timely management of acute pain in children with SCD.

Effect of Hbs on accuracy of pulse oximetry in blood oxygen saturation level measurement among adult patients with sickle cell disease

This study was conducted to investigate the effect of Hbs on accuracy of pulse oximetry in blood oxygen saturation level measurement among adult patients with sickle cell disease crises in Shahid Mohammadi Hospital of Bandar Abbas during 2017. For this cross-sectional study, the statistical population included all patients with sickle cell disease who were hospitalizes in emergency department of Shahid Mohammadi Hospital of Bandar Abbas during the second half of 2017. At first, pulse oximetry was performed on subjects and then the arterial blood samples were taken to analyze arterial blood gas (ABG) according to the protocol. Blood samples were taken from each subject for electrophoresis and determination of Hbs level. The mean results of pulse oximetry on patients was 97.69 ± 1.57, with the lowest 90% and the highest 98%. In contrast, the oxygen content of the ABG analysis varied from 78 to 93%, and the mean of these results was 87.54 ± 3.54. The Hbs level of electrophoresis on patients was 72.78 ± 8.12%. The difference between the blood oxygen saturation level in the blood obtained by pulse oximetry and arterial blood gas analysis was less than 10%. The findings showed that the oxygen saturation level in the blood measured by using two techniques of pulse oximetry and AGB analysis was significantly different. It is advisable to use more accurate techniques to estimate the oxygen saturation level in the blood and to determine the rate of hypoxia.

Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease.

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Acute Orbitopathy Manifesting as Periorbital Cellulitis in Sickle Cell Disease

Sickle cell disease is a hemoglobinopathy that results in paroxysmal vascular occlusion and tissue infarction that can manifest in a plurality of tissues. Vasoocclusive crises in sickle cell disease commonly involve bone marrow of the long bones and vertebrae. Involvement of bones with less marrow space, including the bones of the orbit, is reported rarely in the literature and can closely mimic orbital cellulitis, both clinically and radiologically. The present case is a 3 years old boy, a known case of sickle cell disease, who presented with what was thought to be orbital cellulitis and was treated accordingly. Subtle radiologic features of sickle cell orbitopathy were initially overlooked, resulting in an incorrect diagnosis and a treatment delay for the patient. Correctly treated most cases resolve with no adverse effects. This case highlights the importance of maintaining a high index of suspicion in patients with known sickle cell disease, even when the presentation is not classic.

Bariatric Surgery Impact on Sickle Cell Disease Pain Crisis: A Case Report

Sickle cell disease (SCD) is an autosomal genetic blood disorder resulting in multiple end-organ complications. Malnutrition is a stress factor that can cause a SCD crisis. Bariatric surgery is a weight reduction surgery that involves the binding or removing a part of the stomach or resecting and re-routing the small intestine to a small stomach pouch. It is known to cause malnutrition and stress. Malnutrition affects more than two billion people of all ages worldwide due to different causes. Long-term deficiency of micronutrients leads to reduced immunity, leukopenia, and diseases affecting the psychological, skeletal, and central nervous system. We here present the case of a 20-year-old woman with SCD and class III obesity. She underwent sleeve gastrectomy in 2018 following psychological distress caused by being severely overweight. She had mild SCD pain, but after the bariatric surgery, it became severe, requiring morphine treatment and monthly exchange transfusion beside the NSAID which become not much effective as before bariatric surgery. Our findings show that bariatric surgery, which leads to a stressful condition, can aggravate the SCD pain crisis, thereby highlighting the need for alternative methods of weight reduction in these patients. Controlled studies are required for the proper assessment of bariatric surgery in SCD.

Hemopexin Replacement Therapy Protects Sickle Cell Disease Mice from Acute Kidney Injury

Acute kidney injury (AKI) is a major clinical concern during episodes of acute chest syndrome and vaso-occlusive crisis in sickle cell disease (SCD). AKI increases the risk of chronic kidney disease (CKD) and end stage renal disease (ESRD). We previously showed that alpha-1-microglobulin (A1M), a low affinity heme-binding protein that carries heme for renal clearance is elevated in patients and mice with homozygous SCD (SS). Hemopexin (Hx), which primarily scavenges circulating heme to the liver, is exhausted in SCD. In this study, we explored the idea that acquired Hx deficiency in SCD is a risk factor for AKI development in SCD. We studied mice with a global knockout of Hx with no detectable plasma Hx at baseline. Plasma A1M was significantly elevated in the Hx-/-mice compared to control (Hx+/+) mice (n=5; p&amp;lt;0.01). We then transplanted whole bone marrow cells from SS mice into Hx+/+and Hx-/-mice to create bone marrow chimeric SSHx+/+and SSHx-/-mice with SCD phenotype. The chimeras had elevated plasma A1M compared to recipient littermates (Hx+/+and Hx-/-) and low baseline glomerular filtration rate (GFR). Modest elevation of circulating heme with infusion of hemin (20 μmoles/kg bw) worsened GFR and caused severe AKI. Next, to determine whether hemin induced AKI is attenuated by elevation of circulating Hx, we infused SS mice with purified Hx, and control SS mice with either purified A1M or vehicle immediately prior to the hemin challenge. We observed improved GFR in the Hx-treated SS mice, while vehicle and A1M-treated mice suffered 23% and 39% loss of GFR respectively compared to their baseline. In agreement with the GFR data, the levels of several AKI diagnostic markers, plasma creatinine (plasma Cr), urinary albumin-creatinine ratio (uACR) and kidney injury molecule (uKIM-1) were elevated significantly in vehicle and A1M treated mice following hemin challenge. In Hx-treated mice, these biomarkers remained unaltered. Importantly, Hx infusions re-directed excess heme in SS mice to the liver, while A1M infusion significantly increased total heme content in the kidneys. Two-way ANOVA analysis of GFR (p&amp;lt;0.01) and plasma Cr (p&amp;lt;0.001) revealed significant exacerbation of kidney injury in A1M treated SS mice compared to vehicle treated mice. Histopathology of renal tissue showed considerable tissue damage in vehicle and A1M infused SS mice, while Hx treated SS mice kidneys appeared relatively normal. This study provides genetic evidence that hemopexin deficiency promotes AKI development in SCD, and we provide proof-of-principle for hemopexin replacement therapy to treat AKI in SCD. Disclosures Ofori-Acquah: Shire Human Genetic Therapies Inc: Other: Financial Relationship.